Source Citation

Abstract

Objective

To evaluate the effectiveness of boosting oxygen delivery by infusing dobutamine in
critically ill patients.

Design

Randomized controlled trial with follow-up to hospital discharge. The trial was stopped
after the second interim analysis because the intensive care unit (ICU) and in-hospital
mortality differed significantly between groups.

Intervention

50 patients were assigned to dobutamine, 5 to 200 µg/kg/min, until all 3 targets for
cardiac index, oxygen consumption, and oxygen delivery were achieved, unless sinus
tachycardia, tachyarrhythmia, or electrocardiographic evidence of myocardial ischemia
developed, in which case the dose of dobutamine was immediately reduced or discontinued
and then titrated to achieve the highest possible values for cardiac index and oxygen
consumption and delivery. 50 patients were assigned to the control group and received
dobutamine only if the cardiac index was < 2.8 L/min/m2.

Main outcome measures

Main results

21 patients in the control group and all patients in the treatment group received
dobutamine. No difference existed between the treatment and control groups for oxygen
consumption (P = 0.12) or mean arterial blood pressure (P = 0.42), despite a higher cardiac index and level of oxygen delivery in the treatment
group (P < 0.05). Groups were similar for duration of ICU stay (10 d for each group), days
of ventilation (8 d in both groups), and hospitalization (24 in control group vs 19
d in treatment). Although the predicted risk for death (from the APACHE II score)
was 34% for both groups, in-hospital mortality was higher in the treatment group (54%)
when compared with the control group (34%) (P = 0.04) and ICU mortality showed a similar pattern (30% for control group vs 50% for
treatment group, P = 0.04) (Table).

*Abbreviations defined in Glossary; RRI, NNH, and CI calculated from data in article.

Commentary

In this unblinded study of a heterogeneous group of critically ill patients, Hayes
and colleagues evaluated the use of dobutamine to elevate systemic oxygen delivery.
Patients were comparable at baseline, and all randomized patients were included in
the analysis. A unique feature of this study is that patients were only randomized
if they did not achieve supraphysiologic treatment goals after fluid resuscitation.
Thus, the group of patients selected were those not responsive to fluid challenge.
Also, although the intervention in the active group was based on previous recommendations
that were associated with improved outcome, the study protocol may have resulted in
higher doses of inotropes and vasoactive drugs. Patients in the experimental arm received
high-dose dobutamine and 68% received norepinephrine (the latter, though, only to
elevate systemic vascular resistance to low normal values). This may have exacerbated
tissue ischemia and resulted in the high incidence of death attributable to organ
failure.

The Hayes study, taken in the context of other experiments, does not conclude the
ongoing heated debate of whether pharmacologically increasing oxygen delivery in critically
ill patients is beneficial. This study does, however, alert us to the fact that delayed
(even by a few hours after admission), aggressive use of inotropes to maximize oxygen
delivery may be harmful. To date, 6 other randomized controlled trials have been published;
2 reported a significant survival benefit, 2 reported a favorable trend, and 2 showed
no difference between groups. It is interesting to note that the 2 studies showing
a significant reduction in mortality after maximizing tissue oxygen delivery aimed
preoperatively for these supraphysiologic targets. It is also important to note that
inferences based on these previous studies are plagued by problems, such as pseudorandomization,
selection bias, multiple cointerventions, and crossovers. The Hayes study confirms
previous findings that ability to achieve supraphysiologic cardiac index and oxygen
delivery and consumption (either spontaneously or pharmacologically) is a marker for
survival. This is also, however, the first randomized trial showing that attempting
to maximize cardiac output and oxygen delivery may actually do more harm than good.

Overall, the evidence concerning enhancing tissue oxygen delivery for critically ill
patients remains inconclusive. A recent systematic review (1) of 7 randomized controlled trials (RCTs) of interventions designed to achieve supraphysiologic
values of cardiac index and oxygen delivery showed that targetting therapy to supraphysiologic
endpoints in critically ill patients had no significant effect on mortality (relative
risk 0.86, 95% CI 0.62 to 1.20). The 2 trials in which these goals were targetted
preoperatively (2, 3), however, showed potential benefit (relative risk 0.20, CI 0.07 to 0.55) in this
subgroup. One recent RCT from the United Kingdom (4) also showed that in major elective surgery, preoperative increase in oxygen delivery
has a favorable effect on mortality, whereas a recent RCT in septic patients (5) did not find any benefit.